SGK1 inhibition in glia ameliorates pathologies and symptoms in Parkinson disease animal models

Abstract

Astrocytes and microglia are brain‐resident glia that can establish harmful inflammatory environments in disease contexts and thereby contribute to the progression of neuronal loss in neurodegenerative disorders. Correcting the diseased properties of glia is therefore an appealing strategy for treating brain diseases. Previous studies have shown that serum/ glucocorticoid related kinase 1 (SGK1) is upregulated in the brains of patients with various neurodegenerative disorders, suggesting its involvement in the pathogenesis of those diseases. In this study, we show that inhibiting glial SGK1 corrects the pro‐inflammatory properties of glia by suppressing the intracellular NFκB‐, NLRP3‐inflammasome‐, and CGAS‐STING‐mediated inflammatory pathways. Furthermore, SGK1 inhibition potentiated glial activity to scavenge glutamate toxicity and prevented glial cell senescence and mitochondrial damage, which have recently been reported as critical pathologic features of and therapeutic targets in Parkinson disease (PD) and Alzheimer disease (AD). Along with those anti‐inflammatory/neurotrophic functions, silencing and pharmacological inhibition of SGK1 protected midbrain dopamine neurons from degeneration and cured pathologic synuclein alpha (SNCA) aggregation and PD‐associated behavioral deficits in multiple in vitro and in vivo PD models. Collectively, these findings suggest that SGK1 inhibition could be a useful strategy for treating PD and other neurodegenerative disorders that share the common pathology of glia‐mediated neuroinflammation.

Neuroglial Senescence, α-Synucleinopathy, and the Therapeutic Potential of Senolytics in Parkinson’s Disease

“…It has recently been shown that astrocyte and microglia senescence in PD can be mitigated by senolytic treatment with the serum and glucocorticoid related kinase 1 (SGK1) inhibitor GSK-650394 ( Kwon et al, 2021 ). NF-kB transcription factors are responsible for transcribing pro-inflammatory genes, including those for cytokines and chemokines ( Liu et al, 2017 ).…”

“…Through phosphorylation, SGK1 activates NF-kB pathways and promotes inflammatory responses ( Lang and Voelkl, 2013 ). GSK-650394 reduces cytokine levels and SGK1 overexpression boosted cytokine levels in cultured mice astrocytes and microglia from the cortex and ventral midbrain ( Kwon et al, 2021 ). Furthermore, Nurr1 and Foxa2 downregulate Sgk1 in the mouse cultured glia, as shown in microarray and RNA-seq data ( Kwon et al, 2021 ).…”

Parkinsons Disease-Like Neuropathology and Phenotype Following Induction of Oxidative Stress and Inflammation in the Brain

“…The role of obvious apoptosis-related transcripts like Casp9 (caspase 9) in neurodegeneration is well documented [59]. Enhanced transcription of Sgk1 (Serum/Glucocorticoid Related Kinase 1) is upregulated in the brains of PD patients [60]. Another upregulated transcript is Sparc (Secreted Protein Acidic and Cysteine-Rich) which has been reported to be expressed diff erently in Parkinson's LRRK2-derived astrocytes from iPSC [61].…”

Therapeutic Potential of Ursolic Acid in Cancer and Diabetic Neuropathy Diseases

“…Hence, UA may be considered a potential therapeutic drug for neurological diseases [88]. PD is a chronic progressive neurodegenerative disease described by motor and nonmotor features [127][128][129][130]. Its increasing degenerative effects on muscle regulation and mobility have a key clinical result for caregivers, families and patients [131].…”